Identification of Novel RAS Signaling Therapeutic Vulnerabilities in Diffuse Intrinsic Pontine Gliomas.

Abstract

Diffuse intrinsic pontine gliomas (DIPG) are incurable brain tumors with an aggressive onset. Apart from irradiation, there are currently no effective therapies available for patients with DIPG, who have a median survival time of less than one year. Most DIPG cells harbor mutations in genes encoding histone H3 (H3K27M) proteins, resulting in a global reduction of H3K27 trimethylation and activation of oncogenic signaling pathways. Here we show that the H3K27M mutations contribute to RAS pathway signaling, which is augmented by additional RAS activators including PDGFRA. H3K27M mutation led to increased expression of receptor tyrosine kinases (RTK). A RAS pathway functional screen identified ERK5, but not ERK1/2, as a RAS pathway effector important for DIPG growth. Suppression of ERK5 decreased DIPG cell proliferation and induced apoptosis in vitro and in vivo. In addition, depletion or inhibition of ERK5 significantly increased survival of mice intracranially engrafted with DIPG cells. Mechanistically, ERK5 directly stabilized the proto-oncogene MYC at the protein level. Collectively, our data demonstrate an underappreciated role of H3K27M in RAS activation and reveal novel therapeutic targets for treating DIPG tumors. SIGNIFICANCE: These findings identify the H3K27M mutation as an enhancer of RAS activation in DIPG and ERK5 as a novel, immediately actionable molecular target. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/16/4026/F1.large.jpg.

• Authors: Robert F Koncar, Brittany R Dey, Ann-Catherine J Stanton, Nishant Agrawal, Michelle L Wassell, Lauren H McCarl, Abigail L Locke, Lauren Sanders, Olena Morozova-Vaske, Max I Myers, Ronald L Hamilton, Angel M Carcaboso, Gary Kohanbash, Baoli Hu, Nduka M Amankulor, James Felker, Madhuri Kambhampati, Javad Nazarian, Oren J Becher, C David James, Rintaro Hashizume, Alberto Broniscer, Ian F Pollack, Sameer Agnihotri
• Journal: Cancer research (Cancer Res) Vol. 79 Issue 16 Pg. 4026-4041 (08 15 2019) ISSN: 1538-7445 [Electronic] United States
• PMID: 31201162 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• Aniline Compounds
• BIX 02189
• Histones
• Indoles
• MAS1 protein, human
• Proto-Oncogene Mas
• Receptor, Platelet-Derived Growth Factor alpha
• MAPK7 protein, human
• Mitogen-Activated Protein Kinase 7
• ras Proteins
• Lysine

Topics

• Aniline Compounds (pharmacology)
• Animals
• Brain Stem Neoplasms (drug therapy, genetics, metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation (genetics)
• Diffuse Intrinsic Pontine Glioma (drug therapy, genetics, metabolism, pathology)
• Female
• Gene Expression Regulation, Neoplastic
• Genes, myc
• Histones (genetics, metabolism)
• Humans
• Indoles (pharmacology)
• Lysine (genetics, metabolism)
• Male
• Mice, SCID
• Mitogen-Activated Protein Kinase 7 (antagonists & inhibitors, genetics, metabolism)
• Mutation
• Neural Stem Cells (metabolism)
• Proto-Oncogene Mas
• Receptor, Platelet-Derived Growth Factor alpha (genetics, metabolism)
• ras Proteins (genetics, metabolism)